Clefts of the lip and/or palate are among the most common and easily diagnosed birth defects, and can provide a model for complex trait analysis. Family and twin studies have clearly indicated a genetic role in the etiology of cleft lip and palate, but environmental components play a major role, as well. The environmental risk factors identified (e.g., medications, alcohol, smoking, nutritional deficiencies) are weak (O.R. < 1.5). Similarly, genetic analysis has not as yet identified any strong single gene as playing a major role in clefting. In the previous funding cycle of this proposal, we were able to analyze a large sample for both case parent triads and case controls for environmental data and molecular analysis. The initial submission took advantage of the cleft population that has been studied in Denmark since the 1930s and which provided an ethnically homogenous population, as well as an extensive historic database to carry out the studies. In this resubmission, we will now partner with parallel efforts underway in Norway, and take advantage of a well-established collaboration between Norway, Denmark and the United States. In addition, we have added a state-of-the-art epidemiologic analytic team based at the National Institutes of Environmental and Health Sciences who are developing new analytic tools to take advantage of the sample sizes available. Finally, advances in molecular technologies--particularly the identification of single nucleotide polymorphisms (SNPs)--have afforded the opportunity to carry out genotyping at an unprecedented level for a group of genes which have a high prior probability of being directly involved in clefting. The combination of these unique resources affords the opportunity to study cleft lip and palate in detail. In this project, we will characterize 50 candidate genes and 150 SNP markers within those genes in a total of 600 case parent triads for both isolated cleft palate and cleft lip with or without cleft palate. Positive findings from this initial analysis will then be confirmed in a case control analysis using over 800 cases and 2800 controls. Confirmed findings at this stage will then undergo statistical analysis with an emphasis on gene-gene interaction and, eventually, studies of gene-environment interaction. This project will also set the stage for our use of two large cohort studies taking place in Denmark and Norway in which 200,000 consecutive pregnancies will be ascertained, and detailed epidemiologic, environmental, and biological data made available for studies of clefting. This study will provide a new level of understanding for a complex birth defect trait.